Phosphorylation targets of DYRK1A. The Hsa21-encoded kinase DYRK1A has been shown to phosphorylate a multitude of targets, which have been implicated in a number of biological processes and DS-associated phenotypes, including endocytosis and AD. 

Context in source publication

Context 1

... suggests that these genes are unlikely to be candidates for the dosage-sensitive genes underlying DS phenotypes in the tissues investigated. Trisomy of Hsa21 is associated with a small number of conserved features, occurring in all individuals, including mild-to-moderate learning disability, craniofacial abnormalities and hypotonia in early infancy (17). Although these phenotypes are always found in people with DS, the degree to which an individual is affected varies. Additionally, trisomy of Hsa21 is also associated with variant phenotypes that only affect some people with DS, including atrioventricular septal defects (AVSDs) in the heart, acute megakaryoblastic leukaemia (AMKL) and a decrease in the incidence of some solid tumours. This phenotypic variation is likely to be caused by a combination of environmental and genetic causes. Genetic polymorphisms in both Hsa21 and non-Hsa21 genes may account for much of this variation. Genome-wide association studies to identify these polymorphisms constitute a promising strategy to gain novel insights into the pathology of DS. A central goal of DS research is to understand which of the genes on Hsa21, when present in three copies, lead to each of the different DS-associated phenotypes, and to elucidate how increased expression leads to the molecular, cellular and physiological changes underlying DS pathology. Two distinct approaches are being taken to address these issues. First, genomic association studies, such as that recently published by Lyle et al (18)., may point to genes that play an important role in pathology. Secondly, a number of animal models of Hsa21 trisomy have been generated. Recent advances in chromosome engineering have led to the establishment of mice trisomic for different sets of mouse genes syntenic to Hsa21, and a mouse strain, Tc(Hsa21)1TybEmcf (Tc1), carrying most of Hsa21, as a freely segregating chromosome (Fig. 1) (19 – 27). These strains are being used both to map dosage-sensitive genes on Hsa21 and to understand patho- logical mechanisms. Here, we review recent advances in the understanding of DS-associated phenotypes and the development of therapeutic strategies to treat them. Trisomy of Hsa21 has a significant impact on the development of many tissues, most notably the heart and the brain. A recent paper has suggested that trisomy of the Hsa21 genes, dual- specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A ( DYRK1A ) and regulator of calcineurin 1 ( RCAN1 ), may have an impact on the development of multiple tissues (28). DYRK1A is a priming kinase that facilitates the further phosphorylation of numerous proteins by other kinases (Fig. 2) (29 –38). It is up-regulated in a number of tissues from people with DS (39,40). RCAN1 is a regulator of the protein phosphatase calcineurin (41). Crabtree and colleagues hypothesized that trisomy of these two genes may act synergistically to alter signalling via the NFAT family of transcription factors (28). In an independent study, increased DYRK1A gene dosage was shown to decrease the expression level of RE1-silencing transcription factor ( REST ) (42). As REST is required both to maintain pluripotency and to facilitate neuronal differentiation, a perturbation in REST expression may alter the development of many cell types. Indeed, over-expression of DYRK1A in some animal models is associated with a number of phenotypes, including heart defects and abnormal learning and memory (28,33,43–45). However, not all animal models that over-express DYRK1A exhibit these defects, suggesting that polymorphisms or differences in the expression of other genes influence the outcome of DYRK1A trisomy (24). Trisomy of Hsa21 is associated with a reduction in brain volume, the size of the hippocampus and cerebellum being particularly affected (46 – 49). A similar phenotype is also observed in the Ts65Dn model (50). Recent studies have started to elucidate the developmental mechanisms underlying these important phenotypes. Trisomic granule cell precursors from the cerebellum have a reduced mitogenic response to the morphogen sonic hedgehog (51). This was shown to underlie the reduced number of cerebellar granular cells observed in the Ts65Dn mouse model of DS. Hypocellularity in the hippocampus also has a developmental origin (52,53). Abnormalities in cell-cycle length, apoptosis and neocortical neurogenesis have been shown to contribute to this phenotype (53 –55). The reduced level of neurogenesis in Ts65Dn adult hippocampus can be ameliorated by treatment with the anti- depressant fluoxetine, which is a serotonin reuptake inhibitor (56). Fluoxetine may promote neurogenesis via a number of potential mechanisms, including a direct effect on serotonin levels or via an indirect effect on behaviour. Whether this drug has similar effect during embryonic development has yet to be determined. Ts65Dn pups exhibit a delay in attaining several developmental milestones, such as forelimb grip and the righting reflex, mimicking the developmental delay observed in babies with DS (57). A recent report has demonstrated that treatment of Ts65Dn embryos with two neuroprotective pep- tides reduced the delay in achieving a number of sensory and motor developmental milestones during early post-natal development (58). People with DS exhibit craniofacial dysmorphology, including a mandible of reduced size. This phenotype is also observed in the Ts65Dn and Tc1 models (26,59). In the Ts65Dn model, craniofacial dysmorphology is present from early post-natal development and may be related to specific changes in bone development (60,61). The small mandible in people with DS may be caused by migration and proliferation defects in mandible precursor (neural crest) cells in the developing embryo, related to an altered response to sonic hedgehog (62). All people with DS have a mild-to-moderate learning disability. Over-expression of a number of Hsa21 genes, including DYRK1A, synaptojanin 1 and single-minded homologue 2 (SIM2), results in learning and memory defects in mouse models, suggesting that trisomy of these genes may contribute to learning disability in people with DS (43,45,63,64). In addition, trisomy of neuronal channel proteins, such as G- protein-coupled inward-rectifying potassium channel subunit 2 ( GIRK2 ), may also influence learning in people with DS (65 – 67). Recent work has demonstrated that trisomy of a segment of mouse chromosome 16 ( Mmu16 ) containing 33 genes including DYRK1A , GIRK2 and SIM2 was necessary, but not sufficient for the hippocampal-based learning deficits in the Ts65Dn mouse model (68). These data indicate that trisomy of multiple Hsa21 genes is required for the deficits in learning associated with DS. Moreover, Hsa21 trisomy may independently impact on multiple learning pathways. Recent work on the Tc1 transchromosomic mouse model of DS has examined in detail the learning pathways affected by trisomy of Hsa21 (26,69). The Tc1 transchromosomic model exhibits abnormalities in short-term but not in long-term hippocampal-dependent learning. The learning deficits are correlated with specific abnormalities in long-term potentiation (LTP) in the dentate gyrus of the hippocampus. LTP is an electrophysiological process proposed to be the cellular basis of learning and memory (70). These data provide insight into which learning mechanisms may be affected by Hsa21 trisomy and can be used to further understand their genetic cause. Structural abnormalities may contribute to these deficits in learning and memory. Indeed, a correlation between specific synaptic abnormalities in the hippocampus of the Ts(16C-tel)1Cje ...